Apoptosis of neointimal smooth muscle cells is a well-recognized component of the pathogenesis of neointimal lesions. In advanced atherosclerotic plaques, smooth muscle cell death predisposes to plaque destabilization, resulting in plaque rupture and subsequent thrombosis. Conversely, restenotic lesions may develop as a consequence of reduced apoptotic signaling. Although TNF and FAS receptors contribute to smooth muscle cell apoptosis in vascular lesions, recent evidence from our laboratory identified the neurotrophin receptor, p75NTR, as a novel growth factor/receptor system, which can induce apoptosis of vascular smooth muscle cells. P75NTR and neurotrophins are selectively expressed in areas of atherosclerotic lesions where there is increased smooth muscle cell apoptosis and the neurotrophins are potent apoptotic agents for p75-expressing smooth muscle cells. We propose that ligand-induced activation of p75NTR in vascular lesions is a major contributor to the apoptosis of neointimal smooth muscle cells. The overall aim of this proposal is to dissect the signal transduction pathways mediating smooth muscle cells apoptosis. Specifically, in Specific aim 1, we will define the signal transduction pathways regulating Caspase activation and apoptosis of smooth muscle cells in response to ligand-induced activation of p75NTR and compare them to those induced during FAS-mediated apoptosis. The identification of common critical pathways mediating smooth muscle cell apoptosis would provide potential therapeutic targets for treatment of chronic vascular injury. Studies in the second specific aim will determine whether neurotrophin-induced apoptosis by p75NTR is modulated by concomitant expression of the second class of neurotrophin receptor, the trk family of receptor tyrosine kinases. Finally, in Specific Aim III, we will define the role of the p75NTR on lesion development in murine models of vascular injury in mice, which do not express p75NTR. These studies will allow us to test whether the absence of p75NTR increases neointimal formation following vascular injury.